Abstract Number: PB0242
Meeting: ISTH 2020 Congress
Background: Histidine-rich glycoprotein (HRG) is an abundant plasma protein that binds factor (F) XIIa and inhibits FXII autoactivation and FXIIa-mediated activation of FXI. Polyphosphate (PolyP) is a potent procoagulant released by activated platelets that serve as a physiological activator of the contact pathway. Previously, we showed that HRG binds DNA and neutralizes its procoagulant activity, so the capacity of HRG to bind polyanions may endow it with a regulatory role in thrombosis. Therefore, we hypothesized that HRG would also bind PolyP and attenuate its procoagulant activity.
Aims: To determine whether HRG binds PolyP and attenuates its prothrombotic activity in a FXII dependent manner.
Methods: Binding of immobilized short-chain PolyP (70-mer) to HRG was measured using an enzyme-linked immunosorbent assay (ELISA). PolyP-induced thrombin generation was performed in HRG-depleted and control plasma. HRG-knockout (HRG-/-) and wild-type (WT) mice were given intraperitoneal PolyP (100 mg/kg) or an equivalent volume of saline. Blood collected at intervals was used for the determination of thrombin generation and thrombin-antithrombin complexes (TAT) levels. After 60 min, lung perfusion and fibrin deposition were assessed with Evans blue dye and immunohistochemistry, respectively. To examine the role of FXII, HRG-/- and WT mice were given a FXII-specific antisense oligonucleotide (ASO) (40 mg/kg/wk) for four weeks before PolyP administration.
Results: HRG binds PolyP with a Kd value of 152 ± 6 nM. PolyP-induced thrombin generation is 2-fold greater in HRG-depleted plasma than in control plasma. Intraperitoneal PolyP enhances peak thrombin of thrombin generation, increases TAT levels, reduces lung perfusion, and promotes pulmonary fibrin deposition to a greater extent in HRG-/- mice than in WT mice and these effects are attenuated with FXII knockdown.
Conclusions: HRG binds PolyP and attenuates its prothrombotic activity in a FXII dependent manner. These findings provide evidence of another mechanism via which HRG modulates the intrinsic pathway of coagulation.
To cite this abstract in AMA style:Malik R, Zhou J, Fredenburgh J, Revenko A, Weitz J. Histidine-Rich Glycoprotein Attenuates the Prothrombotic Activity of Polyphosphate in a FXII-Dependent Manner [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/histidine-rich-glycoprotein-attenuates-the-prothrombotic-activity-of-polyphosphate-in-a-fxii-dependent-manner/. Accessed May 6, 2021.
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